: In these studies Dr. Shenker will employ a two-tiered approach to determine the cellular and molecular modes of action of each of four immunosuppressive factors (ISFs). The specific aims of this proposal are: 1) To identify the primary cellular target of immunosuppressive factors from: Actinobacillus actinomycetemcomitans (Aa), Treponema denticola, Bacteroides intermedius and Fusobacterium nucleatum; these studies will include assessment of cytokine production, expression of cell surface markers, manipulations; 2) To determine the mode of action for each ISF at the molecular level with particular focus on membrane signal transduction and cell cycling; 3) To isolate and characterize the gene for Aa ISF in order to develop large scale expression systems and to initiate studies on structural analysis; and 4) to monitor these inhibitory agents for their capacity to affect the immune response in vivo utilizing SCID mice reconstituted with a functional human immune system. These studies could lead to a greater understanding of the etiology of periodontal disease. This information could provide a basis for possible early detection and prevention of disease as well as for alternative approaches to therapeutic intervention.